tbuckley/cabot-search huggingface dataset:
Comparative Genomics Reveals Insights into the Divergent Evolution of Astigmatic Mites and Household Pest Adaptations
Authors: Qing Xiong, Angel Tsz-Yau Wan, Xiaoyu Liu, Cathy Sin-Hang Fung, Xiaojun Xiao, Nat Malainual, Jinpao Hou, Lingyi Wang, Mingqiang Wang, Kevin Yi Yang, Yubao Cui, Elaine Lai-Han Leung, Wenyan Nong, Soo-Kyung Shin, Shannon Wing-Ngor Au, Kyoung Yong Jeong, Fook-Tim Chew, Jerome Ho-Lam Hui, Ting-Fan Leung, Anchalee Tungtrongchitr, Nanshan Zhong, Zhigang Liu, Stephen Kwok-Wing Tsui
Journal: Molecular Biology and Evolution (2022)

Abstract Highly diversified astigmatic mites comprise many medically important human household pests such as house dust mites causing ∼1–2% of all allergic diseases globally; however, their evolutionary origin and diverse lifestyles including reversible parasitism have not been illustrated at the genomic level, which hampers allergy prevention and our exploration of these household pests. Using six high-quality assembled and annotated genomes, this study not only refuted the monophyly of mites and ticks, but also thoroughly explored the divergence of Acariformes and the diversification of astigmatic mites. In monophyletic Acariformes, Prostigmata known as notorious plant pests first evolved, and then rapidly evolving Astigmata diverged from soil oribatid mites. Within astigmatic mites, a wide range of gene families rapidly expanded via tandem gene duplications, including ionotropic glutamate receptors, triacylglycerol lipases, serine proteases and UDP glucuronosyltransferases. Gene diversification after tandem duplications provides many genetic resources for adaptation to sensing environmental signals, digestion, and detoxification in rapidly changing household environments. Many gene decay events only occurred in the skin-burrowing parasitic mite Sarcoptes scabiei. Throughout the evolution of Acariformes, massive horizontal gene transfer events occurred in gene families such as UDP glucuronosyltransferases and several important fungal cell wall lytic enzymes, which enable detoxification and digestive functions and provide perfect drug targets for pest control. This comparative study sheds light on the divergent evolution and quick adaptation to human household environments of astigmatic mites and provides insights into the genetic adaptations and even control of human household pests.
Physicians’ Experiences With Mistreatment and Discrimination by Patients, Families, and Visitors and Association With Burnout
Authors: Liselotte N. Dyrbye, Colin P. West, Christine A. Sinsky, Mickey Trockel, Michael Tutty, Daniel Satele, Lindsey Carlasare, Tait Shanafelt
Journal: JAMA Network Open (2022)

Burnout is common among physicians and is associated with suboptimal patient outcomes. Little is known about how experiences with patients, families, and visitors differ by physician characteristics or contribute to the risk of burnout.To examine the occurrence of mistreatment and discrimination by patients, families, and visitors by physician characteristics and the association between such interactions and experiencing burnout.This cross-sectional survey was conducted from November 20, 2020, to March 23, 2021, among US physicians.Mistreatment and discrimination were measured using items adapted from the Association of American Medical College's Graduation Questionnaire with an additional item querying respondents about refusal of care because of the physicians' personal attributes; higher score indicated greater exposure to mistreatment and discrimination.Burnout as measured by the Maslach Burnout Inventory.Of 6512 responding physicians, 2450 (39.4%) were female, and 369 (7.2%) were Hispanic; 681 (13.3%) were non-Hispanic Asian, Native Hawaiian, or Pacific Islander; and 3633 (70.5%) were non-Hispanic White individuals. Being subjected to racially or ethnically offensive remarks (1849 [29.4%]), offensive sexist remarks (1810 [28.7%]), or unwanted sexual advances (1291 [20.5%]) by patients, families, or visitors at least once in the previous year were common experiences. Approximately 1 in 5 physicians (1359 [21.6%]) had experienced a patient or their family refusing to allow them to provide care because of the physician's personal attributes at least once in the previous year. On multivariable analyses, female physicians (OR, 2.33; 95% CI, 2.02-2.69) and ethnic and racial minority physicians (eg, Black or African American: OR, 1.59; 95% CI, 1.13-2.23) were more likely to report mistreatment or discrimination in the previous year. Experience of mistreatment or discrimination was independently associated with higher odds of burnout (vs score of 0 [no mistreatment], score of 1: OR, 1.27; 95% CI, 1.04-1.55; score of 2: OR, 1.70; 95% CI, 1.38-2.08; score of 3: OR, 2.20; 95% CI, 1.89-2.57). There was no difference in the odds of burnout by gender after controlling for experiencing mistreatment and discrimination score and other demographic factors, specialty, practice setting, work hours, and frequency of overnight call.In this study, mistreatment and discrimination by patients, families, and visitors were common, especially for female and racial and ethnic minority physicians, and associated with burnout. Efforts to mitigate physician burnout should include attention to patient and visitor conduct.
The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants
Authors: Liu Cao, Yingjun Li, Sidi Yang, Guanguan Li, Qifan Zhou, Jing Sun, Tiefeng Xu, Yang Yang, Ruyan Liao, Yongxia Shi, Yujian Yang, Tiaozhen Zhu, Siyao Huang, Yanxi Ji, Feng Cong, Yinzhu Luo, Yujun Zhu, Hemi Luan, Huan Zhang, Jingdiao Chen, Xue Liu, Renru Luo, Lihong Liu, Ping Wang, Yang Yu, Fan Xing, Bixia Ke, Huanying Zheng, Xiaoling Deng, Wenyong Zhang, Chuwen Lin, Mang Shi, Chun-Mei Li, Yu Zhang, Lu Zhang, Jun Dai, Hongzhou Lu, Jincun Zhao, Xumu Zhang, Deyin Guo
Journal: Science Translational Medicine (2022)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus driving the ongoing coronavirus disease 2019 (COVID-19) pandemic, continues to rapidly evolve. Because of the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOCs), orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously, we showed that the parent nucleoside of remdesivir, GS-441524, has potent anti-SARS-CoV-2 activity. Here, we report that esterification of the 5'-hydroxyl moieties of GS-441524 markedly improved antiviral potency. This 5'-hydroxyl-isobutyryl prodrug, ATV006, demonstrated excellent oral bioavailability in rats and cynomolgus monkeys and exhibited potent antiviral efficacy against different SARS-CoV-2 VOCs in vitro and in three mouse models. Oral administration of ATV006 reduced viral loads and alleviated lung damage when administered prophylactically and therapeutically to K18-hACE2 mice challenged with the Delta variant of SARS-CoV-2. These data indicate that ATV006 represents a promising oral antiviral drug candidate for SARS-CoV-2.
Factors associated with health‐related quality of life in heart failure in 23 000 patients from 40 countries: results of the <scp>G‐CHF</scp> research programme
Authors: Isabelle Johansson, Kumar Balasubramanian, Shrikant Bangdiwala, Lisa Mielniczuk, Camilla Hage, Sanjib Kumar Sharma, Kelley Branch, Jun Zhu, Kristian Kragholm, Karen Sliwa, Francois Alla, Gerald Yonga, Ambuj Roy, Andres Orlandini, Alex Grinvalds, Tara McCready, Nana Pogosova, Stefan Störk, John J.V. McMurray, David Conen, Salim Yusuf
Journal: European Journal of Heart Failure (2022)
Survival Outcomes Associated With Cytoreductive Nephrectomy in Patients With Metastatic Clear Cell Renal Cell Carcinoma
Authors: Nicholas H. Chakiryan, L. Robert Gore, Richard R. Reich, Rodney L. Dunn, Da David Jiang, Kyle A. Gillis, Elizabeth Green, Ali Hajiran, Lee Hugar, Logan Zemp, Jingsong Zhang, Rohit K. Jain, Jad Chahoud, Philippe E. Spiess, Brandon J. Manley, Wade J. Sexton, Brent K. Hollenbeck, Scott M. Gilbert
Journal: JAMA Network Open (2022)

Level I evidence has failed to demonstrate an overall survival (OS) advantage for cytoreductive nephrectomy in patients with metastatic clear cell renal cell carcinoma (ccRCC) in the modern era, which is at odds with observational studies reporting a marked OS benefit associated with these operations. These observational studies were not designed to adjust for unmeasured confounding.To assess whether cytoreductive nephrectomy is associated with improved OS in patients with metastatic ccRCC.This cohort study identified patients with metastatic ccRCC in the National Cancer Database from January 1, 2006, to December 31, 2016, who received systemic targeted therapy. The analysis was finalized on July 23, 2021.Receipt of cytoreductive nephrectomy.The primary outcome was OS from the date of diagnosis to death or censoring at last follow-up. Distance from the patients' zip code of residence to the treating facility was identified as a valid instrument and was used in a 2-stage residual inclusion instrumental variable analysis. Conventional adjustments for selection bias, multivariable Cox proportional hazards regression, and propensity score matching were performed for comparison. Measured covariates adjusted for in all analyses included age, sex, race, Charlson-Deyo score, facility type, year of diagnosis, clinical T stage, and clinical N stage.The final study population included 12 766 patients (median age, 63 years; IQR, 56-70 years; 8744 [68%] male; 11 206 [88%] White). Cytoreductive nephrectomy was performed in 5005 patients (39%). Conventional adjustments for selection bias demonstrated a significant OS benefit associated with cytoreductive nephrectomy (multivariable Cox proportional hazards regression: hazard ratio [HR], 0.49; 95% CI, 0.47-0.51; propensity score matching: HR, 0.48; 95% CI, 0.46-0.50). Instrumental variable estimates did not demonstrate an association between cytoreductive nephrectomy and OS (HR, 0.92; 95% CI, 0.78-1.09).Instrumental variable analysis did not demonstrate a survival advantage associated with cytoreductive nephrectomy for patients with metastatic ccRCC. This discrepancy likely reflects the fact that surgical indication for cytoreductive nephrectomy is primarily driven by factors that are not commonly measured or available in observational data sets.
A Role for the Vascular Endothelium in Post–Acute COVID-19?
Authors: Laura P.M.H. de Rooij, Lisa M. Becker, Peter Carmeliet
Journal: Circulation (2022)

hile the war against acute coronavirus disease 2019 (COVID-19) is still raging, reports of a long-lasting post-COVID-19 syndrome are surging."Long COVID" progressed from a mere oddity to an acknowledged public health issue worldwide.A formal definition of post-acute COVID-19 syndrome (ie, long COVID) is evolving, and for the purposes of this review, we consider it as persistent symptoms or complications lasting more than 30 days after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.Symptoms of long COVID involve multiple organs and include shortness of breath, fatigue, chest pain, loss of taste and/or smell, and cognitive dysfunction.Studies investigating the incidence of long COVID report broad heterogeneity (likely attributable to variations in study cohorts and long COVID definition/symptoms), and its manifestation may range from ≈30% to a staggering ≥80% of all SARS-CoV-2infected patients. 1,2Although there is hope that vaccination may reduce the risk of developing long COVID, studies remain inconclusive thus far.Breakthrough infections frequently occur in vaccinated people and may unfortunately still cause an escalation in long COVID cases.Detection and treatment of long COVID is challenging because the molecular underpinnings of the condition remain largely unknown.
Arginine-mediated gut microbiome remodeling promotes host pulmonary immune defense against nontuberculous mycobacterial infection
Authors: Young Jae Kim, June-Young Lee, Jae Jin Lee, Sang Min Jeon, Prashanta Silwal, In Soo Kim, Hyeon Ji Kim, Cho Rong Park, Chaeuk Chung, Jeong Eun Han, Jee-Won Choi, Euon Jung Tak, Ji-Ho Yoo, Su-Won Jeong, Do-Yeon Kim, Warisa Ketphan, Su-Young Kim, Byung Woo Jhun, Jake Whang, Jin-Man Kim, Hyungjin Eoh, Jin-Woo Bae, Eun-Kyeong Jo
Journal: Gut Microbes (2022)

Nontuberculous mycobacterial pulmonary diseases (NTM-PDs) are emerging as global health threats with issues of antibiotic resistance. Accumulating evidence suggests that the gut–lung axis may provide novel candidates for host-directed therapeutics against various infectious diseases. However, little is known about the gut–lung axis in the context of host protective immunity to identify new therapeutics for NTM-PDs. This study was performed to identify gut microbes and metabolites capable of conferring pulmonary immunity to NTM-PDs. Using metabolomics analysis of sera from NTM-PD patients and mouse models, we showed that the levels of l-arginine were decreased in sera from NTM-PD patients and NTM-infected mice. Oral administration of l-arginine significantly enhanced pulmonary antimicrobial activities with the expansion of IFN-γ-producing effector T cells and a shift to microbicidal (M1) macrophages in the lungs of NTM-PD model mice. Mice that received fecal microbiota transplants from l-arginine-treated mice showed increased protective host defense in the lungs against NTM-PD, whereas l-arginine-induced pulmonary host defense was attenuated in mice treated with antibiotics. Using 16S rRNA sequencing, we further showed that l-arginine administration resulted in enrichment of the gut microbiota composition with Bifidobacterium species. Notably, oral treatment with either Bifidobacterium pseudolongum or inosine enhanced antimicrobial pulmonary immune defense against NTM infection, even with multidrug-resistant clinical NTM strains. Our findings indicate that l-arginine-induced gut microbiota remodeling with enrichment of B. pseudolongum boosts pulmonary immune defense against NTM infection by driving the protective gut–lung axis in vivo.
Prediabetes and Diabetes Screening Eligibility and Detection in US Adults After Changes to US Preventive Services Task Force and American Diabetes Association Recommendations
Authors: Michael Fang, Dan Wang, Justin B. Echouffo-Tcheugui, Elizabeth Selvin
Journal: JAMA (2022)

This cross-sectional study using NHANES data assesses the proportion of asymptomatic US adults eligible for screening based on new vs current US Preventive Services Task Force and American Diabetes Association screening guidelines, overall and among those with prediabetes or undiagnosed diabetes.
Diagnostic potential of extracellular vesicles in meningioma patients
Authors: Franz L Ricklefs, Cecile L Maire, Kathrin Wollmann, Lasse Dührsen, Krystian D Fita, Felix Sahm, Christel Herold-Mende, Andreas von Deimling, Katharina Kolbe, Mareike Holz, Leonie Bergmann, Marceline M Fuh, Hartmut Schlüter, Malik Alawi, Rudolph Reimer, Sven Peine, Markus Glatzel, Manfred Westphal, Katrin Lamszus
Journal: Neuro-Oncology (2022)

Extracellular vesicles (EVs) play an important role in cell-cell communication, and tumor-derived EVs circulating in patient blood can serve as biomarkers. Here, we investigated the potential role of plasma EVs in meningioma patients for tumor detection and determined whether EVs secreted by meningioma cells reflect epigenetic, genomic, and proteomic alterations of original tumors.EV concentrations were quantified in patient plasma (n = 46). Short-term meningioma cultures were established (n = 26) and secreted EVs were isolated. Methylation and copy number profiling was performed using 850k arrays, and mutations were identified by targeted gene panel sequencing. Differential quantitative mass spectrometry was employed for proteomic analysis.Levels of circulating EVs were elevated in meningioma patients compared to healthy individuals, and the plasma EV concentration correlated with malignancy grade and extent of peritumoral edema. Postoperatively, EV counts dropped to normal levels, and the magnitude of the postoperative decrease was associated with extent of tumor resection. Methylation profiling of EV-DNA allowed correct tumor classification as meningioma in all investigated cases, and accurate methylation subclass assignment in almost all cases. Copy number variations present in tumors, as well as tumor-specific mutations were faithfully reflected in meningioma EV-DNA. Proteomic EV profiling did not permit original tumor identification but revealed tumor-associated proteins that could potentially be utilized to enrich meningioma EVs from biofluids.Elevated EV levels in meningioma patient plasma could aid in tumor diagnosis and assessment of treatment response. Meningioma EV-DNA mirrors genetic and epigenetic tumor alterations and facilitates molecular tumor classification.
An antiplatelet response gene expression signature is associated with bleeding
Authors: Kevin A Friede, Rachel A Myers, Jordan Gales, Ilya Zhbannikov, Thomas L Ortel, Svati H Shah, William E Kraus, Geoffrey S Ginsburg, Deepak Voora
Journal: Cardiovascular Research (2022)

Gene expression biosignatures may hold promise to individualize antiplatelet therapy in conjunction with current guidelines and risk scores. The Aspirin Response Signature (ARS) score is comprised of a weighted sum of correlated, pro-thrombotic gene transcripts measured in whole blood. In prior work where volunteers were exposed to aspirin 325 mg daily, higher ARS score was associated with lower platelet function; separately, in a clinical cohort of patients, higher ARS scores were associated with increased risk of adverse cardiovascular events. To better understand this apparent paradox, we measured ARS gene expression and score in volunteers to determine aspirin dose-response and ticagrelor relationships with ARS score and separately in patients to assess whether ARS is associated with incident bleeding.Blood samples were collected from volunteers (N = 188) who were exposed to 4 weeks of daily aspirin 81 mg, daily aspirin 325 mg, and/or twice-daily ticagrelor 90 mg. ARS scores were calculated from whole blood RNA qPCR, and platelet function and protein expression were assessed in platelet-rich plasma. In mixed linear regression models, aspirin 81 mg exposure was not associated with changes in ARS gene expression or score. Aspirin 325 mg exposure resulted in a 6.0% increase in ARS gene expression (P = 7.5 × 10-9 vs. baseline, P = 2.1 × 10-4 vs. aspirin 81 mg) and an increase in expression of platelet proteins corresponding to ARS genes. Ticagrelor exposure resulted in a 30.7% increase in ARS gene expression (P < 1 × 10-10 vs. baseline and each aspirin dose) and ARS score (P = 7.0 × 10-7 vs. baseline, P = 3.6 × 10-6 and 5.59 × 10-4 vs. aspirin 81 and 325 mg, respectively). Increases in ARS gene expression or score were associated with the magnitude of platelet inhibition across agents. To assess the association between ARS scores and incident bleeding, ARS scores were calculated in patients undergoing cardiac catheterization (N = 1421), of whom 25.4% experienced bleeding events over a median 6.2 years of follow-up. In a Cox model adjusting for demographics and baseline antithrombotic medication use, patients with ARS scores above the median had a higher risk of incident bleeding [hazard ratio 1.26 (95% CI 1.01-1.56), P = 0.038].The ARS is an Antiplatelet Response Signature that increases in response to greater platelet inhibition due to antiplatelet therapy and may represent a homeostatic mechanism to prevent bleeding. ARS scores could inform future strategies to prevent bleeding while maintaining antiplatelet therapy's benefit of ischaemic cardiovascular event protection.
NHS data breaches: a further erosion of trust
Authors: Natalie Banner
Journal: BMJ (2022)

NHS data breaches: a further erosion of trust Natalie Banner former lead for Understanding Patient DataThe BMJ has uncovered failures by NHS data users to comply with the terms of their agreements for managing and using data they received from NHS Digital. 1 The audits did not uncover evidence of malicious use, of selling data, or causing harm to patients.But that does not detract from the fact that in several cases, data was stored and used in breach of contracts in which the public are expected to trust.
Time to evolve: predicting engineered T cell-associated toxicity with next-generation models
Authors: Emmanuel Donnadieu, Maik Luu, Miriam Alb, Brigitte Anliker, Silvia Arcangeli, Chiara Bonini, Biagio De Angelis, Rashmi Choudhary, David Espie, Anne Galy, Cam Holland, Zoltán Ivics, Chahrazade Kantari-Mimoun, Marie Jose Kersten, Ulrike Köhl, Chantal Kuhn, Bruno Laugel, Franco Locatelli, Ibtissam Marchiq, Janet Markman, Marta Angiola Moresco, Emma Morris, Helene Negre, Concetta Quintarelli, Michael Rade, Kristin Reiche, Matthias Renner, Eliana Ruggiero, Carmen Sanges, Hans Stauss, Maria Themeli, Jan Van den Brulle, Michael Hudecek, Monica Casucci
Journal: Journal for ImmunoTherapy of Cancer (2022)

Despite promising clinical results in a small subset of malignancies, therapies based on engineered chimeric antigen receptor and T-cell receptor T cells are associated with serious adverse events, including cytokine release syndrome and neurotoxicity. These toxicities are sometimes so severe that they significantly hinder the implementation of this therapeutic strategy. For a long time, existing preclinical models failed to predict severe toxicities seen in human clinical trials after engineered T-cell infusion. However, in recent years, there has been a concerted effort to develop models, including humanized mouse models, which can better recapitulate toxicities observed in patients. The Accelerating Development and Improving Access to CAR and TCR-engineered T cell therapy (T2EVOLVE) consortium is a public–private partnership directed at accelerating the preclinical development and increasing access to engineered T-cell therapy for patients with cancer. A key ambition in T2EVOLVE is to design new models and tools with higher predictive value for clinical safety and efficacy, in order to improve and accelerate the selection of lead T-cell products for clinical translation. Herein, we review existing preclinical models that are used to test the safety of engineered T cells. We will also highlight limitations of these models and propose potential measures to improve them.
Comment on Use of Biologic vs Synthetic Mesh for Single-stage Repair of Contaminated Ventral Hernias—Reply
Authors: Michael J. Rosen, Clayton Petro, Ajita S. Prabhu
Journal: JAMA Surgery (2022)

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